Central Annals of Psychiatry and Mental Health

Short Communication *Corresponding author

Yoram Barak, Department of Psychological Medicine,

Treatment Options for Psychotic Dunedin School of Medicine, PO Box 913, Dunedin, New
Zealand, Email: Yoram.Barak@otago.ac.nz
Submitted: 06 December 2016

Depression in Older People: Accepted: 23 February 2017

Published: 24 February 2017

Focused Literature review by Copyright © 2017 Barak et al.

ISSN: 2374-0124

New Zealand Psychogeriatric OPEN ACCESS

Team Keywords
• Psychotic depression
• Delusions
Matthew Croucher1, Igor Plopsky2, Shani Pridan2, and Yoram • Depression
• Comorbidity
Barak1*
1
The University of Otago Medical School, New Zealand
2
The Sackler School of Medicine, Tel-Aviv University, Israel

Abstract
Background: Psychotic major depressive disorder (PMDD) is complex with poor prognosis, reported in 15% to 25% of episodes with higher rates amongst
older inpatients. There is little data on effective pharmacological treatment of PMDD.
Method: A critical review from a focused literature search was conducted. A literature search of controlled trials from: EMBASE (1970- ), MEDLINE (1950- )
and PsycINFO (1960-) was undertaken. Two authors (SP and YB) independently extracted the data.
Results: Of 386 studies 13 RCTs encompassing1, 359 participants fulfilled inclusion criteria. Of these 556 (41%) were participants in mifepristone trials
that proved negative. Only 2 RCT included older patients. Findings suggest combining antidepressant and antipsychotic medications is advantageous in PMDD.
This is supported by case series and uncontrolled studies. The practice of antidepressant monotherapy cannot be supported in older adults.
Conclusions: Further studies of pharmacological treatment of PMDD in older people are sorely needed.

INTRODUCTION suffering from MDD reported psychotic features with a prevalence

Psychotic major depressive disorder (PMDD) is a severe
form of MDD linked to adverse outcomes such as suicide,
longer inpatient stay, disability, low probability of placebo
response, longer duration of depression and recurrence of
psychotic features in subsequent episodes and overall worse
prognosis than other forms of MDD [1,2]. PMDD is defined as
a depressive episode with psychotic features (delusions and/
or hallucinations) in the context of a unipolar major depressive
disorder. As shorter time to severe relapse was demonstrated in
a large European survey wherein patients with depression were
treated with an antipsychotic medication, the authors concluded
that simultaneous antipsychotic medication use may be a proxy
marker for treatment resistant and psychotic depression [3].
Psychotic depression is not infrequent. The rates of PMDD
are reported to be in the range of 14% -25% [4]. In the US
Epidemiologic Catchment Area Study [5], 14% of participants
suffering from MDD had previous episodes with psychotic
features. Furthermore, In a US study of hospitalized in patients
suffering from depression, 25% met the criteria for PMDD [6].
In a European broad population study, 18.5% of respondents
of PMDD of 0.4% being one-fifth that of MDD [7].
Patients suffering from PMDD can be an exceptional challenge
to treating clinicians as their needs are quite different from those
of MDD patients due to substantial physical comorbidity and
dissimilarities in response to therapy. PMDD is diverse and its
etiology is complex. Treatment of PMDD is currently only loosely
based on guidelines. Lamentably, there is a considerable scarcity
of literature involving evidence-based clinical practice guidelines
and randomized controlled trials in individuals suffering from
PMDD. To date meager research was published focusing on the
use of second generation antipsychotics for PMDD patients [8].
Treatment guidelines for PMDD are lacking and the evidence is
limited regarding the most effective pharmacological treatment.
The commonly employed treatment regimens are: combination
of an antidepressant plus an antipsychotic, monotherapy with
an antidepressant and monotherapy with an antipsychotic.
The 2015 Cochrane review concluded that PMDD is profoundly
understudied, limiting confidence in the conclusions drawn.
Some evidence indicates that combination therapy with an
antidepressant plus an antipsychotic is more effective than either
treatment alone or placebo. However the authors emphasized

Cite this article: Croucher M, Plopsky I, Pridan S, Barak Y (2017) Treatment Options for Psychotic Depression in Older People: Focused Literature review by
New Zealand Psychogeriatric Team Ann Psychiatry Ment Health 5(1): 1094.

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that evidence is limited for mono therapy with an antidepressant
or with an antipsychotic [9].
There are only a small number of treatment studies in older
PMDD patients. The rates of PMDD are higher in older people and
they respond poorly to treatment with medication [10].
The 2015 Cochrane review analyzed only 2 studies from
the last decade and the majority of studies analyzed used
a first generation antipsychotic. For the second generation
antipsychotics the authors analyzed only for 3 olanzapine and 1
quetiapine studies. The present brief review aims to emphasize
recent studies focusing on the pharmacological treatment of
PMDD in older people.
METHODS
Approach to the reviewing process
This was based in part on the approach recently advocated
by Catts and O’Toole [11]. Briefly, the clinical issue reviewed was
selected because the authors considered it decidedly relevant to
the clinical practice of psychiatrists treating PMDD and likely to
impact on health outcomes and its contentious nature is reflected
in divergences across guidelines.
This critical review results from a of focused literature
search. Although a systematic review would have been desirable,
a critical review approach was the feasible way to integrate
the literature. Selection of material was strongly weighted by
relevance [11].
The following bibliographic databases: EMBASE (1970-
), MEDLINE (1950-) and PsycINFO (1960-) were searched.
Bibliography of all studies and relevant reviews were screened.
Two review authors (SP and YB) independently extracted the
data.
Inclusion criteria: For studies to be analyzed in the present
review were: (1) randomized controlled trials (RCTs), (2) PMDD
diagnosis in all or a subgroup of patients, (3) use of rating scales
to quantify depression and/or psychosis, (4) sample size > 20
and (5) publication in the last 10 years.
Exclusion criteria: (1) Dementia of any kind (2) age younger
than 18 years.
Efficacy assessments included change from baseline after
treatment with psychotropic medication. We used intent-to-treat
data and assessed remission rates as the major outcome.
Response and remission criteria are in agreement with those
used in other published studies [12], and are considered to be
clinically meaningful by clinicians.
It is important to note that studies with the novel agent
Mifepristone were also analyzed.
RESULTS
Our search identified 386 abstracts, but only 13 RCTs with a
total of 1,359 participants are included in the present review in
accordance with inclusion criteria.
Due to clinical heterogeneity, few direct comparisons
were possible. The main outcome in the published studies was
Ann Psychiatry Ment Health 5(1): 1094 (2017)
Barak et al. (2017)
Email:
reduction of severity depression or achieving remission (HAM-D
< 7) of depression, not of psychosis. It is important to note that
risk of bias is substantial: there were differences between studies
with respect to diagnosis, differences in treatment interventions
(a variety of antidepressants and antipsychotics) and different
outcome criteria.
The highest remission rates were reported in the 2
antipsychotic monotherapy trials: Olanzapine - 63% and
Risperidone - 55%
Antidepressant monotherapy
Only two studies were reported. In the first, the authors
administered Sertraline 50-200 mgs/daily for 8 weeks. There
were 25 participants. Remission was achieved by only 32% of
patients. The second study compared the efficacy of imipramine
and high-dose venlafaxine in depressed inpatients. There were
no significant differences in the primary outcome measures.
However, when analyzing a subpopulation of patients without
psychotic features a significant difference was found: 5 of 34
(14.7%) patients on imipramine were remitters compared to 12
of 31 (38.7%) patients on venlafaxine [13].
Antipsychotic monotherapy
In the only one study reported Risperidone 0.5-1.8 mgs/
daily was administered for 4 weeks. There were 20 participants.
Remission was achieved by 55% of patients.
An important indirect contribution comes from the Bergen
Psychosis Project (BPP). The hypothesis underlying the BPP is
that most effectiveness studies indicated positive effect on mood
of some second generation antipsychotics (SGAs). The BPP is a
24-month, pragmatic, randomized, head-to-head comparison of
olanzapine, quetiapine, risperidone and ziprasidone in patients
acutely admitted with psychosis. It is important to note that
the BPP is not funded by any industry stakeholder. The aim of
the study was to investigate whether distinct anti-depressive
effects exist amongst SGAs. A total of 226 patients were included.
A significant time-effect showed a steady decay in depressive
symptoms in all medication groups. There was no substantial
difference in anti-depressive effectiveness among olanzapine,
quetiapine, risperidone or ziprasidone in this clinically relevant
sample of patients acutely admitted to hospital for symptoms of
psychosis. The drawback to generalizing these conclusions to
PMDD patients is that there were only 23 PMDD patients in the
sample while the overwhelming majority were patients suffering
from schizophrenia spectrum disorders [14].
Antipsychotic + Antidepressant
This was the largest group of studies despite limited evidence
for the efficacy of combination pharmacotherapy and no positive
trials in older PMDD patients. Five studies employed the
following combinations: Haloperidol + Venlafaxine, Quetiapine +
Venlafaxine, 2 studies focusing on Olanzapine + Fluoxetine and
one study focusing on Olanzapine + sertraline.
There were 630 participants in total treated for 7-14 weeks.
Remission was not statistically different in the Haloperidol +
Venlafaxine study nor in one of the two Olanzapine + Fluoxetine
studies. However, Olanzapine was superior to Olanzapine +
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Fluoxetine in one study with a 66% remission rate and Quetiapine
+ Venlafaxine was superior to Venlafaxine monotherapy.
In the largest study to date focusing on remission rates
of PMDD and comparing those treated with a combination of
atypical antipsychotic medication plus an SSRI with those treated
with antipsychotic monotherapy 259 participants were enrolled.
Of these 142 were older participants. After 12 weeks of treatment
olanzapine + sertraline combination was associated with higher
remission rates than  olanzapine and placebo. In the whole
sample 42% of subjects who underwent combination therapy
achieved remission compared with 24% of subjects treated with
monotherapy. This held true for the older subgroup [15].
Mifepristone monotherapy
Four studies of the “Antiglucocorticoid” [type II glucocorticoid
receptor antagonist (GR-II)] compound were published. In the
three studies wherein treatment duration was 8 weeks there
were a total of 103 participants. Remission was not achieved in 2
studies and in the smaller (N=20) study, 55% of patients achieved
remission. In the fourth study mifepristone was administered for
brief 7 days duration only in comparison to placebo. The sample
size was the largest to date with 433patients meeting the criteria
for PMDD. The fraction of responders randomized to mifepristone
did not statistically differ from placebo [16].
It is of interest to note that although not specifying psychotic
features the latest metyrapone study (blocks cortisol synthesis by
reversibly inhibiting steroid 11β-hydroxylase) has demonstrated
that augmentation of antidepressant therapy with a drug that
targets the HPA axis appears to be ineffective in improving
response to treatment. The authors thus concluded that
metyrapone augmentation of antidepressants is not effectual in
a broadly representative population of patients with treatment-
resistant depression and currently is not an option for patients
with treatment-resistant depression in routine clinical practice
[17].
DISCUSSION
Individuals with depression or anxiety disorder reported
twice the prevalence of psychotic experiences than in people
without these disorders. The presence of psychosis in individuals
with depression is commonly associated with a poorer prognosis
and, therefore, early treatment requires attention and may be
advantageous for the course of psychosis expression [18]. It is
unfortunate that little “real-world” data is available to guide
treatment decisions for patients suffering from PMDD.
In 2008 a case series of older patients with PMDD was
published [19]. Combination treatment for 5 weeks with
amisulpride and antidepressants demonstrated resolution
of psychotic symptoms in all the patients involved. In the only
2 randomized, controlled trials of acute treatment of older
patients with PMDD combination therapy of a second generation
antipsychotic and an antidepressant showed superiority over
placebo. An earlier study by Mulsant and colleagues in 2001 [20]
included an older patients sample with a mean age of 72 years.
The researchers completed a randomized study comparing the
efficacy of an antidepressant alone versus an antidepressant plus
a neuroleptic in the treatment of late-life PMDD. Thirty patients
Ann Psychiatry Ment Health 5(1): 1094 (2017)
Barak et al. (2017)
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received nortriptyline for at least 4 weeks combined with either
perphenazine (N = 14) or placebo (N = 16).Rates of resolution of
both depression and psychosis were higher in the combination
group but did not reach statistical significance. In the largest
published twelve-week, double-blind, randomized, controlled
trial of 259 subjects with PMDD treatment with olanzapine and
sertraline was associated with higher remission rates during
the trial than olanzapine and placebo. Combination therapy was
equally superior in both younger (OR, 1.25; 95% CI, 1.05-1.50;
P = .02) and older adults (OR, 1.34; 95% CI, 1.09-1.66; P = .01)
[14]. Finally, the BPP [13], included only 23 PMDD patients in
the sample of which only 14 were older and thus generalization
of antipsychotic monotherapy for PMDD from this project is ill
advised.
We may cautiously make the following statements;
monotherapy strategies for PMDD have mixed reports in
the literature with little evidence of success. Early studies
demonstrated that TCAs or conventional antipsychotics were
inadequate mono therapies. The present analysis does not
follow the PRISMA’s parameters for systematic review & meta-
analysis http://www.prisma-statement.org/. For that reason
recommendations should be cautiously interpreted. The present
review focused on studies published in the last decade and thus
SGAs and SSRIs or SNRIs are mostly analyzed. There is a “signal”
that antidepressant monotherapy is ineffective. The novel
strategy of antagonizing the GR-II receptor has also failed to
show convincing effects. Combination of an antipsychotic and an
antidepressant demonstrate better outcome in older people but
studies’ limitations are pronounced.
An attempt to better understand the clinically important
broader dimensions of clinical characteristics of PMDD, through
multivariate analysis, in a pure sample of elderly unipolar
delusional depressives as well as to test their external validity
against a set of demographic, anamnestic and psychopathological
validators was published in 2009 [21]. Principal Component
Analysis resulted in the extraction of five factors, jointly
accounting for 69.7% of the total variance. The five factors were
interpreted as representing the dimensions of delusional strength,
acute upsetting, delusional organization, incomprehensibility
and incitation to actions. Overall, the findings contribute to the
further elucidation of major clinical dimensions of delusions in
PMDD in the elderly and the testing of their external validity [20].
Studies focusing on treatment response of the various psychotic
factors in PMDD to antipsychotic medications will inform us
further of the best pharmacological options.
The evidence base for the ideal clinical practice regarding
PMDD is inadequate. The degree of consensus among international
treatment guidelines on PMDD were recently reviewed [22]. The
nine international treatment guidelines considered in the review
have opposing opinions on the optimal treatment for PMDD: 6
of 9 suggest antidepressant plus antipsychotic combination
therapy, 3 of 9 recommend antidepressant monotherapy and 5 of
9 find electroconvulsive therapy suitable as first line treatment.
These results indicate that treatment algorithms regarding PMDD
are highly heterogeneous. This finding emphasizes the need for
further studies on the treatment of PMDD [22].
In conclusion, large randomized trials are called for to inform
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clinicians on the best treatment for older patients suffering from
PMDD. In the meanwhile we tentatively suggest combination
treatment be the first line in managing this severe condition.
KEY POINTS
1. Psychotic major depressive disorder (PMDD) is a severe
form of MDD often associated with adverse outcomes
reported in up to 25% of episodes with higher rates
recorded for older inpatients.
2. There is little data on the most effective pharmacological
treatment of PMDD in older people.
3. Of 386 studies published in the last decade 13 RCTs with
a total of 1,359 participants were identified and of these
only 2 included older patients.
4. The available evidence suggests that a combination of an
antidepressant and an antipsychotic may be advantageous
in treating PMDD in older people.
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Croucher M, Plopsky I, Pridan S, Barak Y (2017) Treatment Options for Psychotic Depression in Older People: Focused Literature review by New Zealand Psycho-
geriatric Team Ann Psychiatry Ment Health 5(1): 1094.
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